Method and system for sterilization of a cryogen

ABSTRACT

A system and method for sterilizing a cryogen is provided. In the disclosed embodiment a liquid cryogen is first vaporized and subsequently compressed prior to undergoing sterilization using biological filters. The compressed, sterilized cryogen vapor is then pre-cooled, preferably with the cryogen being vaporized, to produce a partially condensed, cool, sterile cryogen stream and then further condensed using the liquid cryogen to produce a sterilized liquid cryogen.

CROSS REFERENCE TO RELATED APPLICATIONS

None

TECHNICAL FIELD

This invention relates to the production of sterile cryogen such assterile nitrogen, and more particularly, to a method and system forsterilizing a cryogen that demonstrates improved thermodynamicefficiency and improved recovery of the cryogen.

BACKGROUND

During pharmaceutical manufacturing operations, temperature control ofvarious reactions and process steps is often essential. Such temperaturecontrol is often achieved through cryogenic cooling of selected processreactions or freezing of pharmaceutical or bio-pharmaceutical materials.In some applications, the cryogenic cooling or freezing may be carriedout by an indirect heat exchange process using a liquid or vaporcryogen, such as nitrogen. However, a direct heat exchange processinvolving direct contact of the liquid or vapor cryogen with thematerial to be cooled is preferred due to the more efficient transfer ofrefrigeration from the cryogen to the material.

Any material that comes into direct contact with various pharmaceuticalor bio-pharmaceutical products is often required to be sterile. Liquidor vapor nitrogen, for example, may be used to cool various processreactions or freeze various pharmaceutical or bio-pharmaceuticalmaterials using a direct heat exchange process provided the liquidnitrogen is sterile. Although bacteria and other microorganisms whichmay have been introduced during storage and distribution of the liquidnitrogen are generally inactive at the cryogenic temperatures of liquidnitrogen, such bacteria and other microorganisms can then return toactivity when exposed to normal conditions. Cryogenic temperaturesalone, therefore, are not enough to bring about sterility.

Previous cryogen sterilization processes, such as those disclosed inU.S. Pat. No. 5,737,926 has a relatively low recovery (e.g. the ratio ofsterile liquid nitrogen produced to nitrogen used) and less than optimumthermal efficiency. What is needed is an improved cryogen sterilizationsystem and process that demonstrates higher cryogen recovery and greaterthermal efficiency.

SUMMARY OF THE INVENTION

In one aspect, the present invention may be characterized as a method ofsterilizing a cryogen comprising the steps of: (a) vaporizing a liquidcryogen; (b) compressing the cold cryogen vapor; (c) sterilizing thecompressed cryogen vapor; (d) pre-cooling the compressed, sterilecryogen vapor to produce a partially condensed, cool, sterile cryogenstream; and (e) further condensing the partially condensed, cool,sterile cryogen stream to produce a sterilized cryogen.

The invention may also be characterized as a cryogen sterilizationsystem comprising: a source of cryogen vapor; a compressor adapted forcompressing the cryogen vapor to a prescribed pressure; a biologicalfilter adapted for sterilizing the compressed cryogen vapor; apre-cooler adapted to receive the compressed, sterile cryogen vapor andproduce a partially condensed, cool, sterile cryogen stream; and asecondary condenser adapted for further condensing the partiallycondensed, cool, sterile cryogen stream to produce a sterilized cryogen.

In another aspect, the invention may broadly be characterized as amethod of sterilizing a cryogen comprising the steps of: (a) compressinga cryogen vapor; (b) sterilizing the compressed cryogen vapor; (c)pre-cooling the compressed, sterile cryogen vapor to produce a partiallycondensed, cool sterile cryogen stream; and (d) further condensing thepartially condensed cool sterile cryogen stream to produce a sterilizedcryogen.

The above and other aspects, features and advantages of the presentinvention will be more apparent from the following more detaileddescription taken in conjunction with the drawing.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a schematic representation of one preferred embodiment of theinvention for producing cryogenic sterile cryogen.

DETAILED DESCRIPTION

The most commonly used sterile cryogen from a commercial standpoint issterile nitrogen. Accordingly, the invention will be described in detailwith reference to FIG. 1 and in conjunction with the production ofsterile nitrogen. However, it should be understood that the describedembodiments are equally applicable to sterilization of other cryogenssuch as argon, helium, hydrogen, carbon dioxide, oxygen, etc. Referringnow to FIG. 1, liquid nitrogen 10 is passed from a source of liquidnitrogen such as a storage tank 12, through conduit means into firstheat exchanger or evaporator 14 which is located within cold box 16.Liquid nitrogen 10 has a nitrogen concentration of at least 60 molepercent, preferably at least 95 mole percent, and is at a pressuregenerally within the range of from 15 to 250 pounds per square inchabsolute (psia) and at a temperature of −160 degrees Centigrade or less.Preferably, the temperature of the liquid nitrogen is the saturationtemperature of the liquid nitrogen at the corresponding pressure. Coldbox 16 is an insulated container which preferably also houses a secondheat exchanger or condenser/liquifier 18.

Preferably, the first and second heat exchangers are plate-finconfiguration heat exchangers and may be separate units or may beintegrated as a single heat exchange system, which avoids unneededinterconnecting conduits and generally reduces the volume of the coldbox 16 and associated insulation requirement.

Within evaporator 14, the liquid nitrogen 10 is vaporized to producecold nitrogen vapor 20 having a temperature generally within the rangeof from about −30 degrees Centigrade to about −80 degrees Centigrade ator near the originating pressure. This cold nitrogen vapor 20 is passedto compressor 25 wherein it is compressed to a pressure of about 70 to360 psia and the heat of compression raises the temperature within therange of from about −20 degrees Centigrade to about 30 degreesCentigrade to produce warm, compressed nitrogen vapor 30 suitable foruse with biological filters. Preferably the warm, compressed nitrogenvapor 30 is at ambient temperature or at least a temperature thatexceeds the embrittlement temperature and glass transition temperatureof the biological filter materials.

Warm, compressed nitrogen vapor 30 is passed to a biological filtermodule 32 wherein it is sterilized to produce sterile, warm, compressednitrogen vapor 40. In the embodiment of the invention illustrated inFIG. 1, the compressed nitrogen fluid is passed to filter module 32containing a plurality of biological filters 34 and emerges as sterile,warm, compressed nitrogen vapor 40. Steam 50 may also be used forsterilization purposes in conjunction with the biological filters.

Sterile, warm, compressed nitrogen vapor 40 is passed by conduit fromthe biological filters 34 of filter module 32 to evaporator 14 whereinthe heat within the sterile, warm, compressed nitrogen vapor 40 is usedto vaporize the liquid nitrogen 10 through an indirect heat exchange. Inthe course of this heat exchange the sterile, warm, compressed nitrogenvapor 40 is cooled to produce a partially condensed, cool, sterilenitrogen stream 60 having a temperature generally within the range offrom about −157 degrees Centigrade to about −193 degrees Centigrade.Because of the higher pressure of the sterile nitrogen stream, the vaporis partially condensed which results in improved thermal efficiency ofthe system as well as improved nitrogen recovery rates.

The partially condensed, cool, sterile nitrogen stream 60 is then passedfrom the evaporator 14 to the secondary condenser/liquifier 18. Withinthe secondary condenser/liquifier 18, the cool, partially condensedsterile nitrogen stream 60 is further condensed by indirect heatexchange to produce cryogenic sterile liquid nitrogen 70. The cryogenicsterile liquid nitrogen 70 may be used directly, in whole or in part,for cooling and/or freezing purposes, or may be passed, in whole or inpart, to storage tank 72 prior to use. FIG. 1 also shows a divertedstream of liquid nitrogen 80 that is reduced in pressure by passagethrough valve 82 and subsequently passed into the secondarycondenser/liquifier 18 as the low pressure, nitrogen cooling stream 90wherein it is vaporized to effect the aforesaid further condensation ofthe cool, partially condensed, sterile nitrogen vapor 60. Resultinggaseous nitrogen 99 is then withdrawn from secondary condenser/liquifier18 and vented as appropriate.

Using the present embodiment, the re-liquification or condensation ofthe sterile nitrogen is accomplished in two steps. Through use of thevapor compressor, the sterile, warm, compressed nitrogen vapor partiallycondenses during the pre-cooling step provided the pressure of thesterilized vapor is greater than the saturation pressure of the liquidnitrogen that is being vaporized. Using the two-step condensationprocess, the thermal efficiency of the sterilization system is improvedby extracting more refrigeration from the vaporizing nitrogen streamwhich in turn improves the overall recovery.

The following tables summarize an example of the present inventionwherein sterile liquid nitrogen is produced at the rate of 850 lb/hr(11,902 cf/hr at NTP). The example is of an embodiment of the inventionsimilar to that illustrated in FIG. 1 and the stream numbers shown inTable 1 correspond to the reference numerals shown in FIG. 1. Theexample is presented for illustrative purposes and is not intended to belimiting.

TABLE 1 Example of Nitrogen Sterilization System Operation TemperatureFlowrate Present N₂ Pressure (degrees Vapor (CFH- Sterilization System(psia) C.) Fraction NTP) Liquid Nitrogen (10) 90 −176.4 0.0281 11,902Cold Nitrogen Vapor 87 −52.3 1.0000 11,902 (20) Compressed Nitrogen 20026.8 1.0000 11,902 Vapor (30) Sterile Nitrogen 190 26.7 1.0000 11,902Vapor (40) Partially Condensed, 187 −165.4 0.4300 11,902 Cool, SterileNitrogen Stream (60) Sterile Liquid 184 −165.7 0.0000 11,902 Nitrogen(70) Low Pressure Cooling 100 −175.0 0.0094 4,457 Stream (90) GaseousNitrogen (99) 97 −175.4 1.0000 4,457

TABLE 2 Nitrogen Sterilization System Comparative Results Prior Art N₂Sterilization (U.S. Pat. No. Present N₂ Parameter 5,737,926)Sterilization Sterile Liquid 5,500 Liters/min 5,500 Liters/min NitrogenOutput Supply Nitrogen Input 12,500 Liters/min 7,559 Liters/min PowerInput Heater: 21 kW Compressor: 9 kW UA - Refrigeration 336 W/C 957 W/CRecovery (Evaporator) UA - Refrigeration 3130 W/C 688 W/C Recovery(Condenser/Liquefier)

As seen in Table 1, in order to produce about 5500 liters/min of sterileliquid nitrogen the prior art system used approximately 12500 liters/minof supply liquid nitrogen resulting in a nitrogen recovery of about 44%.The balance of about 7000 liters/min of nitrogen is vented. The powerconsumption used by the heater in the prior art nitrogen sterilizationsystem is about 21 kW. Conversely, the presently disclosed embodiment ofthe liquid nitrogen sterilization system uses about 7559 liters/min ofsupply liquid nitrogen to produce about 5500 liters/min of sterileliquid nitrogen. This results in a nitrogen recovery of about 73%. Also,the power input to the compressor is only about 9 kW resulting insignificant power savings and the associated cost savings compared tothe prior art nitrogen sterilization systems.

Although the invention has been described in detail with reference to acertain preferred embodiment, those skilled in the art will recognizethat there are other embodiments of the invention within the spirit andthe scope of the claims. For example, as discussed above, other sterilecryogens may be produced with the practice of this invention. It isrecognized that the sterile cryogen produced, e.g. sterile nitrogen, maybe pure, e.g. 100 percent nitrogen, or may be a mixture containing lessthan 100 percent of the cryogen species.

From the foregoing, it should be appreciated that the present inventionthus provides a method and system for the sterilization of a cryogen.While the invention herein disclosed has been described by means ofspecific embodiments and processes associated therewith, numerousmodifications and variations can be made thereto by those skilled in theart without departing from the scope of the invention as set forth inthe claims or sacrificing all its material advantages.

1. A method of sterilizing a cryogen comprising the steps of: vaporizinga liquid cryogen to produce a cold cryogen vapor; compressing the coldcryogen vapor to produce a compressed cryogen vapor; sterilizing thecompressed cryogen vapor to produce a compressed, sterile cryogen vapor;pre-cooling the compressed, sterile cryogen vapor to produce a partiallycondensed, cool, sterile cryogen stream; and further condensing thepartially condensed, cool, sterile cryogen stream to produce asterilized cryogen.
 2. The method of claim 1 wherein the step ofcompressing the cold cryogen vapor further comprises compressing thecold cryogen vapor to a pressure greater than the saturation pressure ofthe liquid cryogen that is vaporized.
 3. The method of claim 2 whereinthe step of compressing the cold cryogen vapor further comprisescompressing the cold cryogen vapor to a pressure of between about 70 psiand about 360 psi.
 4. The method of claim 1 wherein the cold cryogenvapor is further warmed to a temperature of between about −20 degreesCentigrade to about 30 degrees Centigrade during the compressing step.5. The method of claim 1 wherein the step of further condensingcomprises passing the partially condensed, cool, sterile cryogen streamthrough an indirect heat exchanger together with a portion of the liquidcryogen.
 6. The method of claim 1 wherein the cryogen is selected fromthe group consisting of nitrogen, hydrogen, helium, oxygen, and argon.7. The method of claim 1 wherein the step of sterilizing the compressedcryogen vapor further comprises passing the compressed cryogen vaporthrough a biological filter.
 8. A cryogen sterilization systemcomprising: a source of cryogen vapor; a compressor fluidically coupledto the source of cryogen vapor and adapted for compressing the cryogenvapor to a prescribed pressure; a biological filter fluidically coupledto the compressor and adapted for sterilizing the compressed cryogenvapor; a pre-cooler fluidically coupled to the biological filter andadapted to receive the compressed, sterile cryogen vapor and produce apartially condensed, cool, sterile cryogen stream; and a secondarycondenser fluidically coupled to the pre-cooler and adapted for furthercondensing the partially condensed, cool, sterile cryogen stream toproduce a sterilized cryogen.
 9. The system of claim 8 wherein thesource of cryogen vapor further comprises: a source of liquid cryogen;and an evaporator fluidically coupled to the source of liquid cryogenand adapted to vaporize the liquid cryogen.
 10. The system of claim 9wherein the pressure of the compressed, cryogen vapor is greater thanthe saturation pressure of the liquid cryogen that is vaporized.
 11. Thesystem of claim 8 wherein the pressure of the compressed, cryogen vaporis between about 70 psi and 360 psi.
 12. The system of claim 8 whereinthe cryogen vapor is at a temperature of between about −20 degreesCentigrade to about 30 degrees Centigrade prior to entering thebiological filter.
 13. The system of claim 8 wherein the cryogen isselected from the group consisting of nitrogen, hydrogen, helium,oxygen, and argon.
 14. The system of claim 8 further comprising astorage tank fluidically coupled to the secondary condenser and adaptedfor storing the sterile cryogen.
 15. A method of sterilizing a cryogencomprising the steps of: compressing a cryogen vapor; sterilizing thecompressed cryogen vapor to produce a compressed, sterile cryogen vapor;pre-cooling the compressed, sterile cryogen vapor to produce a partiallycondensed, cool sterile cryogen stream; and further condensing the coolsterile cryogen stream to produce a sterilized cryogen.
 16. The methodof claim 15 wherein the step of compressing the cryogen vapor furthercomprises compressing the cryogen vapor to a pressure of between about70 psi and about 360 psi.
 17. The method of claim 15 wherein the coldcryogen vapor is further warmed to a temperature of between about −20degrees Centigrade to about 30 degrees Centigrade during the compressingstep.
 18. The method of claim 15 wherein the cryogen is selected fromthe group consisting of nitrogen, hydrogen, helium, oxygen, and argon.